Effect of Proinflammatory Cytokines on the Interplay between Roxithromycin, HMR 3647, or HMR 3004 and Human Polymorphonuclear Neutrophils

Vazifeh, D.; Bryskier, A.; Labro, M. T.

doi:10.1128/aac.44.3.511-521.2000

Cited by 36 publications

(30 citation statements)

References 35 publications

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“…We have previously reported that PKC activation by PMA impairs roxithromycin uptake (22). Similar data are obtained with all erythromycin A derivatives (M. T. Labro, unpublished data).…”

Section: Accumulation Kinetics Of Hmr 3562 and Hmr 3787supporting

confidence: 75%

Cellular Uptake of Two Fluoroketolides, HMR 3562 and HMR 3787, by Human Polymorphonuclear Neutrophils In Vitro

Abdelghaffar

Vazifeh

Labro

2001

Antimicrob Agents Chemother

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We analyzed the cellular accumulation of two new fluoroketolides, HMR 3562 and HMR 3787, by human polymorphonuclear neutrophils (PMN) in vitro. Both compounds were rapidly taken up by PMN, with a cellular-to-extracellular concentration ratio (C/E) of about 141 (HMR 3562) and 117 (HMR 3787) at 5 min, and this was followed by a plateau at 60 to 180 min, with a C/E of >300 at 180 min. Both ketolides were mainly located in PMN granules (about 75%) and egressed slowly from loaded cells (about 40% at 60 min), owing to avid reuptake. Uptake was moderately sensitive to external pH, and activation energy was also moderate (about 70 kJ/mol). As with other macrolides and ketolides, the existence of an active transport system was suggested by (i) the strong interindividual variability in uptake kinetics, suggesting variability in the number or activity of a transport protein; (ii) the saturation kinetics characteristic of a carrier-mediated transport system (V max , about 2,300 ng/2.5 ؋ 10 6 PMN/5 min; K m , about 50 g/ml); (iii) the inhibitory effects of Ni 2؉ (a blocker of the Na ؉ -Ca 2؉ exchanger), phorbol myristate acetate (a protein kinase C activator), and H89 (a protein kinase A inhibitor). Although these two ketolides are more related to HMR 3647 (telithromycin), it is interesting that the presence of a fluoride gave these molecules a cellular pharmacokinetics more like those of HMR 3004 than those of HMR 3647. The macrolide transport system has not been yet elucidated, but our data confirm that, despite variations in chemical structure, all erythromycin A derivatives share a transmembrane transport system.

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“…We have previously reported that PKC activation by PMA impairs roxithromycin uptake (22). Similar data are obtained with all erythromycin A derivatives (M. T. Labro, unpublished data).…”

Section: Accumulation Kinetics Of Hmr 3562 and Hmr 3787supporting

confidence: 75%

Cellular Uptake of Two Fluoroketolides, HMR 3562 and HMR 3787, by Human Polymorphonuclear Neutrophils In Vitro

Abdelghaffar

Vazifeh

Labro

2001

Antimicrob Agents Chemother

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“…Other authors have observed that proinflammatory cytokines (TNF-␣ and IFN-␥) increase macrolide uptake by macrophages or monocytic cell lines and favor the intracellular bactericidal activity of these drugs (30,31,290). Results from our group show a small (about 20%) but significant decrease in the uptake of roxithromycin and ketolides in TNF-␣-and GM-CSF-primed PMNs (397). In addition, these two cytokines decreased the inhibitory effect of HMR 3647 only on oxidant production by PMNs (397).…”

Section: Benzylpyrimidines (Trimethoprim and Analogs)mentioning

confidence: 71%

“…Results from our group show a small (about 20%) but significant decrease in the uptake of roxithromycin and ketolides in TNF-␣-and GM-CSF-primed PMNs (397). In addition, these two cytokines decreased the inhibitory effect of HMR 3647 only on oxidant production by PMNs (397). The clinical relevance of the antioxidant properties of macrolides is difficult to establish.…”

Section: Benzylpyrimidines (Trimethoprim and Analogs)mentioning

confidence: 88%

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

Labro¹

2000

Clinical Microbiology Reviews

151

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“…Activity against intracellular pathogens is the hallmark of macrolides and ketolides, but cellular uptake is required for these drugs to exhibit their activities (13,14). Contrary to macrolides, for which an extended literature on cellular uptake is available, few data are available on the uptake of ketolides (2,3,20,(29)(30)(31). The uptake of the ketolides HMR 3004 (formerly RU 64004) (30) and HMR 3647 (telithromycin) (31) and the fluoroketolides HMR 3562 and HMR 3787 (2) have been analyzed previously.…”

mentioning

confidence: 99%

“…HMR 3004 was used as a comparator drug. In addition, because all erythromycin A derivatives impair oxidant production by phagocytes (1,29,31), we also explored the effect of ABT-773 on this phagocyte function.…”

mentioning

confidence: 99%

Interaction of the New Ketolide ABT-773 (Cethromycin) with Human Polymorphonuclear Neutrophils and the Phagocytic Cell Line PLB-985 In Vitro

Labro

Abdelghaffar

Babin-Chevaye

2004

Antimicrob Agents Chemother

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Whatever the cell type and in contrast to the results obtained with HMR 3004, ABT-773 was mainly located in the cytosol (about 75%) and was rapidly released from loaded cells (about 40% at 5 min), followed by a plateau, likely owing to avid reuptake. Verapamil and H89, an inhibitor of protein kinase A, increased drug efflux. Uptake was sensitive to external pH, and the activation energy was moderate (about 50 kJ/mol). The existence of an active transport system on the PMN membrane was suggested by the following findings: concentrationdependent and saturable uptake (V max , about 10 000 ng/2.5 ؋ 10 6 PMNs/5 min; K m , about 60 g/ml) the inhibitory effects of PMN activators or inhibitors (phorbol myristate acetate, verapamil, Ni 2؉ ) and the significantly decreased levels of accumulation by killed cells and cells treated at low temperatures. In addition, various macrolides impaired ABT-773 uptake, contrary to the findings for the quinolone levofloxacin. ND-and D-PLB also presented saturation kinetics that defined an active transport system (V max and K m values were similar to those obtained with PMNs), but the activation pathway of the carrier system did not seem to be fully functional in ND-PLB. As has been observed with other erythromycin A derivatives, ABT-773 impaired oxidant production by phagocytes in a time-and concentration-dependent manner. These data extend our previous results on the existence of an active transport system common to all macrolides and ketolides, at least in PMNs.Ketolides are a new class of semisynthetic erythromycin A derivatives that are particularly designed to combat respiratory tract pathogens that have acquired resistance to macrolides (32). They are characterized by a 3-keto group instead of the usual ␣-L-cladinose moiety on the erythronolide A ring (6). Telithromycin (HMR 3647) is the first member of this new class to be approved for clinical use. Ketolides possess a broad antibacterial spectrum similar to that of erythromycin A, with additional activity against inducible macrolide-lincosamidestreptogramin B-resistant pathogens (4, 5). Activity against intracellular pathogens is the hallmark of macrolides and ketolides, but cellular uptake is required for these drugs to exhibit their activities (13,14). Contrary to macrolides, for which an extended literature on cellular uptake is available, few data are available on the uptake of ketolides (2,3,20,(29)(30)(31). The uptake of the ketolides HMR 3004 (formerly RU 64004) (30) and HMR 3647 (telithromycin) (31) and the fluoroketolides HMR 3562 and HMR 3787 (2) have been analyzed previously.ABT-773 (cethromycin), a new ketolide developed by Abbott, possesses good activity against gram-positive organisms, some gram-negative organisms, and intracellular bacteria (8,11,18). ABT-773 is active in vitro (9,19,24,27) and in vivo (12, 21) against penicillin-resistant and inducibly erythromycin-resistant staphylococci, streptococci, and pneumococci. No data are yet available, however, on its uptake by phagocytes. In the study described here w...

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Effect of Proinflammatory Cytokines on the Interplay between Roxithromycin, HMR 3647, or HMR 3004 and Human Polymorphonuclear Neutrophils

Cited by 36 publications

References 35 publications

Cellular Uptake of Two Fluoroketolides, HMR 3562 and HMR 3787, by Human Polymorphonuclear Neutrophils In Vitro

Cellular Uptake of Two Fluoroketolides, HMR 3562 and HMR 3787, by Human Polymorphonuclear Neutrophils In Vitro

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

Interaction of the New Ketolide ABT-773 (Cethromycin) with Human Polymorphonuclear Neutrophils and the Phagocytic Cell Line PLB-985 In Vitro

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